This invention relates to a method for stereoselective chemical synthesis, more particularly to a method for stereoselective chemical synthesis by the kinetic resolution of racemic terminal epoxides.
Kinetic resolution, more particularly, hydrolytic kinetic resolution (xe2x80x9cHKRxe2x80x9d) of racemic terminal epoxides, offers efficient and practical commercial access to enantiomerically enriched epoxides and 1,2-diols. The HKR method is catalyzed by cobalt(III) complexes of chiral salen ligands which can be prepared from the corresponding Co(II) complexes or from the direct reaction of salen ligand and Co(II) salts under air or oxygen, see, e.g., U.S. Pat. No. 6,262,278 B1, issued Jul. 17, 2001 for xe2x80x9cSTEREOSELECTIVE RING OPENING REACTIONSxe2x80x9d by Eric N. Jacobsen et. al. and Ready, J. M., Jacobsen, E. N., xe2x80x9cHighly Active Oligomeric (salen)Co Catalysts for Asymmetric Epoxide Ring Opening Reactions,xe2x80x9d J. AM. Chem. Soc. 2001, 123, 2687-2688.
HKR catalyst residues may catalyze undesired reactions and degrade the desired reaction products. For example, Co(III) complexes have been found to catalyze the formation of glycidol from the HKR product 3-chloro-1,2-propanediol, Furrow, M. E., Schaus, S. E., Jacobsen, E. N. xe2x80x9cPractical Access to Highly Enantioenriched C-3 Building Blocks via Hydrolytic Kinetic Resolution,xe2x80x9d J. Org. Chem. 1998, 63, 6776. Undesired side reactions serve to diminish the yield and the chiral and chemical purity of the products, thereby making the manufacture of products of high chiral purity less efficient and more expensive.
The present invention is directed to a method for stereoselective chemical synthesis, comprising: reacting a nucleophile and a chiral or prochiral cyclic substrate, said substrate comprising a carbocycle or a heterocycle having a reactive center susceptible to nucleophilic attack by the nucleophile, in the presence of a chiral non-racemic catalyst to produce a product mixture comprising a stereoisomerically enriched product, wherein the product mixture further comprises a catalyst residue, at least a portion of the catalyst residue is in a first oxidation state and the catalyst residue in the first oxidation state is active in catalyzing degradation of the stereoisomerically enriched product, and chemically or electrochemically changing the oxidation state of the catalyst residue from the first oxidation state to a second oxidation state, wherein catalyst residue in the second oxidation state is less active in catalyzing degradation of the stereoisomerically enriched product than is catalyst residue in the first oxidation state.
The method of the present invention reduces erosion of chiral purity and the chemical transformation to side products of the stereoisomerically enriched product and its corresponding co-product(s) after the HKR. Additionally, the deactivated catalyst is recoverable and recyclable, which leads to a lower cost of the HKR process in the manufacture of key chiral building blocks.
In a first preferred embodiment, the present invention is directed to a method for stereoselective chemical synthesis, comprising reacting a nucleophile and a chiral or prochiral substrate in the presence of a chiral, nonracemic Co(III) salen catalyst to produce a product mixture comprising a stereoisomerically enriched product, wherein the product mixture further comprises a Co(III) salen catalyst residue that is active in catalyzing degradation of the stereoisomerically enriched product, and contacting the product mixture with at least one reducing agent selected from L-ascorbic acid, hydroquinone, hydroquinone derivatives, catechol and catechol derivatives to reduce the Co(III) salen catalyst residue to a Co(II) salen catalyst residue that is less active than the Co(III) salen catalyst residue in catalyzing degradation of the stereoisomerically enriched product.
In a second preferred embodiment, the present invention is directed to a method for stereoselective chemical synthesis, comprising reacting a nucleophile and chiral or prochiral substrate in the presence of a chiral, nonracemic Co(III) salen catalyst to produce a product mixture comprising a stereoisomerically enriched product, wherein the product mixture further comprises a Co(II) salen catalyst residue that is active in catalyzing degradation of the stereoisomerically enriched product, and contacting the product mixture with at least one oxidizing agent selected from hydrogen peroxide, peracids, persulfates, perborates, perchlorates, oxygen and air to oxidize the Co(II) salen catalyst residue to a Co(III) salen residue in the presence of a complexing agent effective in stabilizing the Co(III) salen residue, wherein the stabilized Co(III) salen residue is less active than the Co(II) salen catalyst residue in catalyzing degradation of the stereoisomerically enriched product.
In a preferred embodiment, the step of reacting the nucleophile and cyclic substrate is conducted according to the stereoselective synthesis processes described in U.S. Pat. No. 6,262,278 B1, issued Jul. 17, 2001 for xe2x80x9cSTEREOSELECTIVE RING OPENING REACTIONSxe2x80x9d by Eric N. Jacobsen et. al., the disclosure of which is hereby incorporated herein by reference, provided that the present disclosure shall control in the event of any inconsistencies between the resent disclosure and the ""278 patent.
For convenience, certain terms used in this application are collected here.
The term xe2x80x9cnucleophilexe2x80x9d is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
The terms xe2x80x9celectrophilic atomxe2x80x9d, xe2x80x9celectrophilic centerxe2x80x9d and xe2x80x9creactive centerxe2x80x9d as used herein refer to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. In most (but not all) cases, this will also be the atom from which the leaving group departs.
The term xe2x80x9cleaving groupxe2x80x9d is recognized in the art and as used herein means a chemical moiety that is bonded to the electrophilic center of a substrate and that, in the event that a nucleophile attacks and forms a new bond with the substrate, is replaced by the nucleophile. Exemplary leaving groups include sulfonates, carboxylates, carbonates, carbamates, phosphates and halides.
The term xe2x80x9celectron-withdrawing groupxe2x80x9d is recognized in the art and as used herein means a functionality which draws electrons to itself more than a hydrogen atom would at the same position. Exemplary electron-withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, xe2x80x94CN, chloride, and the like. The term xe2x80x9celectron-donating groupxe2x80x9d, as used herein, means a functionality which draws electrons to itself less than a hydrogen atom would at the same position. Exemplary electron-donating groups include amino, methoxy, and the like.
The term xe2x80x9cchiralxe2x80x9d refers to molecules which have the property of non-superimposability of the mirror image partner, while the term xe2x80x9cachiralxe2x80x9d refers to molecules which are superimposable on their mirror image partner. A xe2x80x9cprochiral moleculexe2x80x9d is a molecule which has the potential to be converted to a chiral molecule in a particular process.
The term xe2x80x9cstereoisomersxe2x80x9d refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. In particular, xe2x80x9cenantiomersxe2x80x9d refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. xe2x80x9cDiastereomersxe2x80x9d, on the other hand, refers to stereoisomers with two or more centers of asymmetry and whose molecules are not mirror images of one another.
The term xe2x80x9cregioisomersxe2x80x9d refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a xe2x80x9cregioselective processxe2x80x9d is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant increase in the yield of a certain regioisomer.
The term xe2x80x9creaction productxe2x80x9d means a compound which results from the reaction of a nucleophile and a substrate. In general, the term xe2x80x9creaction productxe2x80x9d will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
As used herein in reference to a ligand, the term xe2x80x9casymmetricxe2x80x9d means that the ligand comprises chiral centers that are not related by a plane or point of symmetry and/or that the ligand comprises an axis of asymmetry due to, for example, restricted rotation, helicity, molecular knotting or chiral metal complexation.
As used herein in reference to a ligand, the term xe2x80x9ctetradentatexe2x80x9d means that the ligand comprises four Lewis base substituents, which may be selected from, for example, oxygen atoms, sulfur atoms, nitrogen containing substituents, such as amino, amido, or imino groups, phosphorus-containing substituents, such as phosphine or phosphonate groups, and arsenic-containing substituents, such as arsine groups.
As used herein in reference to a complex of a metal atom and a tetradentate ligand, the term xe2x80x9crectangular planarxe2x80x9d refers to a geometric configuration in which, subject to some distortion, the Lewis basic atoms of the complex each lie in substantially the same plane and are in a substantially rectangular arrangement and the metal atom of the complex lies in substantially the same plane.
As used herein to a complex of a metal atom and a tetradentate ligand, the term xe2x80x9crectangular pyramidalxe2x80x9d refers to a geometric configuration in which, subject to some distortion, the Lewis basic atoms of the complex each lie in substantially the same plane and are in a substantially rectangular arrangement and the metal atom of the complex lies above or below the plane.
The term xe2x80x9ccomplexxe2x80x9d as used herein means a coordination compound formed by the union of one or more electronically rich molecules or atoms capable of independent existence with one or more electronically poor molecules or atoms, each of which is also capable of independent existence.
The term xe2x80x9csubstratexe2x80x9d is intended to mean a chemical compound which can react with a nucleophile, or with a ring-expansion regent, according to the present invention, to yield at least one product having a stereogenic center.
The term xe2x80x9ccatalytic amountxe2x80x9d is recognized in the art and means a substoichiometric amount of catalyst relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent catalyst relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent catalyst to reactant.
A xe2x80x9cstereoselective processxe2x80x9d is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product. An xe2x80x9cenantioselective processxe2x80x9d is one which favors production of one of the two possible enantiomers of a reaction product. The subject method is said to produce a xe2x80x9cstereoselectively-enrichedxe2x80x9d product (e.g., enantioselectively-enriched or diastereoselectively-enriched) when the yield of a particular stereoisomer of the product is greater by a statistically significant amount relative to the yield of that stereoisomer resulting from the same reaction run in the absence of a chiral catalyst. For example, an enantioselective reaction catalyzed by one of the subject chiral catalysts will yield an e.e. for a particular enantiomer that is larger than the e.e. of the reaction lacking the chiral catalyst.
An xe2x80x9cenantioselective reactionxe2x80x9d is a reaction that converts an achiral reactant to a chiral, nonracemic product that is enriched in one enantiomer. Enatioselectivity is generally quantified in terms of xe2x80x9cenantiomeric excessxe2x80x9d (xe2x80x9ce.e.xe2x80x9d), defined as:       e    .    e    .    =            [                        (                      A            -            B                    )                          (                      A            +            B                    )                    ]        xc3x97    100  
where A and B are the amounts of enantiomers formed. An enantioselective reaction yields a product with an e.e. greater than zero. Preferred enantioselective reactions yield an e.e. greater than 20%, more preferably greater than 50%, even more preferably greater than 70% and most preferably greater than 80%.
As used herein in reference to a stereoisomerically enriched product, the term xe2x80x9cdegradationxe2x80x9d means a decrease in the yield or the enantiomeric excess of the product.
A xe2x80x9cdiastereoselective reactionxe2x80x9d converts a chiral reactant (which may be racemic or enantiomerically pure) to a product enriched in one diastereomer.
If a chiral reactant is racemic, in the presence of a chiral non-racemic reagent or catalyst, one reactant enantiomer may react more slowly than the other. This is termed a xe2x80x9ckinetic resolutionxe2x80x9d, wherein the reactant enantiomers are resolved by differential reaction rate to yield an enantiomerically enriched product. Kinetic resolution is usually achieved by the use of sufficient reagent to react with only one reactant enantiomer (i.e. one-half mole of reagent per mole of racemic substrate). Examples of catalytic reactions which have been used for kinetic resolution of racemic reactants include the Sharpless epoxidation and the Noyori hydrogenation.
A xe2x80x9cregioselective reactionxe2x80x9d is a reaction which occurs preferentially at one reactive center rather than another reactive center. For example, a regioselective reaction of an unsymmetrically substituted epoxide substrate would cause preferential reaction at one of the two epoxide ring carbons.
The term xe2x80x9cnon-racemicxe2x80x9d with respect to the chiral catalyst, means a preparation of catalyst having greater than 50% of a desired stereoisomer, more preferably at least 75%. xe2x80x9cSubstantially non-racemicxe2x80x9d refers to preparations of the catalyst which have greater than 90% e.e. for a desired stereoisomer of the catalyst, more preferably greater than 95% e.e.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Also for purposes of this invention, the term xe2x80x9chydrocarbonxe2x80x9d is contemplated to include all permissible compounds having at lease one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
The term xe2x80x9calkylxe2x80x9d refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkly groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer carbon atoms in its backbone. Likewise, preferred cycloalkyls have from 4 to 10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring tructure.
Moreover, the term alkyl as used throughout the specification and claims is intended to include both xe2x80x9cunsubstituted alkylsxe2x80x9d and xe2x80x9csubstituted alkylsxe2x80x9d, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl, an alkoxyl, and ester, a phosphoryl, an amine, an amide, an imine, a thiol, a thioether, a thioester, a sulfonyl, an amino, a nitro, or an organometallic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amines, imines, amides, phosphoryls (including phosphonates and phosphines), sulfonyls (including sulfates and sulfonates), and silyl groups, as well as ethers, thioethers, selenoethers, carbonyls (including ketones, aldehydes, carboxylates, and esters), xe2x80x94CF3, xe2x80x94CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, thioalkyls, aminoalkyls, carbonyl-substituted alkyls, CF3, CN, and the like.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.
As used herein, xe2x80x9cnitroxe2x80x9d means xe2x80x94NO2, xe2x80x9chaloxe2x80x9d means xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I, xe2x80x9chydroxylxe2x80x9d means xe2x80x94OH, xe2x80x9ccarboxylxe2x80x9d means xe2x80x94COOH, xe2x80x9caldehydexe2x80x9d means xe2x80x94C(O)H, and xe2x80x9cthioxe2x80x9d means xe2x80x94SH, wherein, in each case, R is H, alkyl or aryl, and the term xe2x80x9corganometallicxe2x80x9d refers to a metallic atom such as mercury, zinc, lead, magnesium or lithium) or a metalloid (such as silicon, arsenic or selenium) which is bonded directly to a carbon atom, such as a diphenylmethoylsilyl group.
Thus, the term xe2x80x9calkylaminexe2x80x9d as used herein means an alkyl group, as defined above, having a substituted or unsubstituted amine attached hereto. In exemplary embodiments, an xe2x80x9caminexe2x80x9d can be represented by he general formula: 
wherein R1 and R2 each independently represent a hydrogen, an alkyl, an alkenyl, xe2x80x94(CH2)mxe2x80x94R3xe2x80x94C(xe2x95x90O)-alkyl, xe2x80x94C(xe2x95x90O)-alkenyl, xe2x80x94C(xe2x95x90O)-alkynyl, xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)mR3, or R1 and R2 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R3 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8.
xe2x80x9cAmidoxe2x80x9d means a substituent group according to the general formula: 
wherein R1 and R2 are as defined above.
xe2x80x9cIminoxe2x80x9d means a substituent group the general formula: 
wherein R1 is as described above, with the added proviso that R1 cannot be H.
xe2x80x9cThioetherxe2x80x9d means a moiety represented by one of xe2x80x94S-alkyl, xe2x80x94S-alkenyl, xe2x80x94S-alkynyl, and xe2x80x94Sxe2x80x94(CH2)mR3, wherein m and R3 are defined above.
The term xe2x80x9ccarbonylxe2x80x9d means xe2x80x94C(O)xe2x80x94. The term xe2x80x9ccarbonyl-substituted alkylxe2x80x9d as used herein means an alkyl group, as defined above, having a substituted or unsubstituted carbonyl group attached thereto, and includes aldehydes, ketones, carboxylates and esters. In exemplary embodiments, the xe2x80x9ccarbonylxe2x80x9d moiety is represented by the general formula: 
wherein X is absent or represents an oxygen or a sulfur, and R4 represents a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mR3, where m and R3 are as defined above. Where X is an oxygen, the formula represents an xe2x80x9cesterxe2x80x9d. Where X is sulfur, the formula represents a xe2x80x9cthioesterxe2x80x9d. Where X is absent, and R4 is not hydrogen, the above formula represents a xe2x80x9cketonexe2x80x9d group. Where the oxygen atom of the above formula is replace by sulfur, the formula represents a xe2x80x9cthiocarbonylxe2x80x9d group.
The terms xe2x80x9calkoxylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propoxy, tert-butoxy and the like. An xe2x80x9cetherxe2x80x9d is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl which renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-alkynyl, xe2x80x94Oxe2x80x94(CH2)mxe2x80x94R3 where m and R3, are described above.
xe2x80x9cPhosphorylxe2x80x9d can in general be represented by the formula: 
wherein Q1 represented S or O, and R5 represents hydrogen, a lower alkyl or an aryl. When used to substitute an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the general formula: 
wherein Q1 represented S or O, and each R5 independently represents hydrogen, a lower alkyl or an aryl, Q2 represents O, S or N.
As used herein the term xe2x80x9cphosphinoxe2x80x9d includes xe2x80x94PR2 and the term xe2x80x9cphosphonatoxe2x80x9d means xe2x80x94P(OR)2, wherein R is H, alkyl, aryl, heterocyclic or polycyclic.
In a preferred embodiment, the xe2x80x9csilylxe2x80x9d moiety which may be substituted on the alkyl can be represented by the general formula: 
wherein each R6 independently represents a hydrogen, an alkyl, an alkenyl, or xe2x80x94(CH2)mxe2x80x94R3, wherein m and R3 defined as above.
Exemplary xe2x80x9cselenoethersxe2x80x9d which may be substituted on the alkyl re selected from one of xe2x80x94Sexe2x80x94(CH2)mxe2x80x94R3, wherein m and R3 are defined as above.
The term xe2x80x9csulfonylxe2x80x9d as used herein means a S(O)2 moiety bonded to two carbon atoms and the term xe2x80x9csulfonatexe2x80x9d as used herein means a sulfonyl group, as defined above, attached to an alkoxy, aryloxy or hydroxy group. Thus, in a preferred embodiment, a sulfonate has the tructure: 
wherein R7 is H, alkyl or aryl.
The term sulfate, as used herein, means a sulfonyl group, as defined above, attached to a hydroxy or alkoxy group. Thus, in a preferred embodiment, a sulfate has the structure: 
wherein R8 and R9 are independently absent, a hydrogen, an alkyl, or an aryl. Furthermore, R8 and R9 taken together with the sulfonyl group and the oxygen atoms to which they are attached, may form a ring structure having from 5 to 10 members.
Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, alkenylamines, alkynylamines, alkenylamides, alkynylamides, alkenylimines, alkyleneimines, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls, alkenoxyls, alkynoxyls, metalloalkenyls and metalloalkynyls.
The term xe2x80x9carylxe2x80x9d as used herein includes 4-, 5-, 6- and 7-membered single-ring aromatic groups which may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiopene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring positions may be substituted with such substituents as described above, for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, aldehydes, esters, or xe2x80x94(CH2)mxe2x80x94R3, xe2x80x94CF3, xe2x80x94CN, or the like, wherein m and R3 are defined as above.
The term xe2x80x9cheteroatomxe2x80x9d as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, phosphorus and selenium.
The terms xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d refer to 4 to 10-membered ring structures, more preferably 5 to 7-membered rings, which ring structures include one to four heteroatoms. Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperrazine, morpholine. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, adehydes, esters, or xe2x80x94(CH2)mR3, xe2x80x94CF3, xe2x80x94CN, or the like, wherein m and R3 are defined as above.
The term xe2x80x9ccarbocyclexe2x80x9d refers generally to ring structures wherein the ring members are each carbon atoms.
The terms xe2x80x9cpolycyclexe2x80x9d or xe2x80x9cpolycyclic groupxe2x80x9d refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocycles) in which two or more carbons are common to two adjoining rings, e.g., the rings are xe2x80x9cfused ringsxe2x80x9d. Rings that are joined through non-adjacent atoms are termed xe2x80x9cbridgedxe2x80x9d rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogens, alkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyls, ethers, thioethers, sulfonyls, selenoethers, ketones, adehydes, esters, or xe2x80x94(CH2)mR3, xe2x80x94CF3, xe2x80x94CN, or the like, wherein m and R3 are defined as above.
A xe2x80x9cbridging substituentxe2x80x9d refers to a substitution at two (or more) sites on the core structure of the catalyst by the same (as opposed to identical) substituent so as to form a covalent bridge between the substitution sites. For example, a bridging substituent may be represented by the general formula or xe2x80x94R10xe2x80x94R11xe2x80x94R12xe2x80x94, wherein R11 is absent or represents an alkyl, an alkenyl, or an alkynyl, preferably C1, to C10, and R10 and R12 are each independently absent or represent an amine, an imine, an amide, a phosphoryl, a carbonyl, a silyl, an oxygen, a sulfonyl, a sulfur, a selenium, or an ester.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds, illustrative substituents include, for example, those described hereinabove. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
In one embodiment, the cyclic substrate comprises at least one compound according to formula (1): 
wherein:
R20, R21, R22 and R23 are each independently an organic or inorganic substituent which form a covalent bond with the carbon atom to which it is attached and which permit the formation of a stable ring structure including Y, and
Y is O, S, xe2x80x94NR24, xe2x80x94C(R25)R26, or has the formula A-B-C, wherein R24 is H, alkyl, carbonyl-substituted alkyl, carbonyl-substituted aryl or sulfonate, R25 and R26 are each independently an electron withdrawing group, A and C are each independently absent or (C1-C5)alkyl, O, S, carbonyl or xe2x80x94NR24 and B is carbonyl, phosphoryl or sulfonyl.
In one preferred embodiment, R20, R21, R22 and R23 are each independently H, hydroxyl, halo, alkyl, alkenyl, alkynyl, amino, imino, amido, nitro, thio, phosphoryl, phosphonato, phosphino, carbonyl, carboxyl, silyl, sulfonyl, or a ketone, aldehyde, ester, thioether, selenoether, or xe2x80x94(CH2)nR27, wherein R27 is aryl, cycloalkyl, cycloalkenyl or heterocyclyl and n is a number wherein 0xe2x89xa6nxe2x89xa68, or may alternatively, be fused with another one of the R20, R21, R22 or R23 substituents to form, together with the carbon atoms to which such substituents are attached, a carbocyclic or heterocyclic ring structure.
In another preferred embodiment, the substrate comprises a cyclic compound containing a electrophilic center and a leaving group, including, for example, epoxides, such as epichlorohydrin, aziridines, such as 1,2-propylene imine, episulfides, such as 1,2-propylene sulfide, cyclic carbonates, such as 1,2-propylene glycol cyclic carbonate, cyclic thiocarbonates, such as 1,2-propylene glycol cyclic thiocarbonate, cyclic phosphates, such as 1,2-propylene glycol cyclic phosphate, cyclic sulfates, such as 1,2-propylene glycol cyclic sulfate, cyclic sulfites, such as 1,2, propylene glycol cyclic sulfite, lactams, such as xcex2-butyrolactam, thiolactams, such as xcex2-butyrothiolactam, lactones, such as xcex2-methyl-y-butyrolactone, thiolactones, such as xcex2-methyl-y-butyrothiolactone, and sultones, such as 1,3-butyrosultone.
In general, any chemical compound having a reactive pair of electrons is suitable as the nucleophile of the present invention. Compounds that, under appropriate reaction conditions, are suitable for use as the nucleophile in the method of the present invention include, for example, hydride; uncharged compounds such as amines, mercaptans, and alcohols, including phenols; charged compounds such as alkoxides, phenoxides, thiolates; organic or inorganic anions, such as carbanions, azide, cyanide, thiocyanate, acetate, formate, chloroformate and bisulfite anions; organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates and acetylides.
In one preferred embodiment, the nucleophile comprises at least one compound selected from water, phenoxides, hydroxides, alkoxides, alcohols, thiols, thiolates, carboxylic acids and carboxylates, and, even more preferably, from water, phenols, particularly silyated phenols, and carboxylic acids.
In one embodiment, the chiral catalyst comprises a complex of an asymmetric tetradentate ligand with a first row transition metal atom, said complex having a rectangular planar or rectangular pyramidal geometry. Suitable tetradentate ligands are those derived from, for example, salens, porphyrins, crown ethers, azacrown ethers, cyclams or phthalocyanines. In a highly preferred embodiment, the tetradentate ligand is derived from a chiral salen or salen-like ligand.
In a preferred embodiment, the metal-asymmetric tetradentate ligand complex comprises at least one chiral metallosalenate according to the structural formula (2): 
or structural formula (3): 
wherein:
R30, R31, R32, R33, R34, R35, Y1, Y2, Y3, Y4, Y5, Y6, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X14, X15, X16, X17, X19 and X20 are each independently H, hydroxyl, halo, alkyl, alkynyl, amino, nitro, thio, imino, amido, phosphoryl, phosphonato, carbonyl, carboxyl, silyl, or an ether, thioether, sulfonyl, selenoether, ketone, aldehyde, ester or xe2x80x94(CH2)nxe2x80x2, xe2x80x94R36, wherein R36 is aryl, cycloalkyl, cycloalkenyl or heterocyclyl or may alternatively, be fused with another one of the R30, R31, R32, R33, R34, R35, Y1, Y2, Y3, Y4, Y5, Y6, X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12, X14, X15, X16, X17, X19 and X20 substituents to form a carbocyclic or heterocyclic ring structure having from 4 to 8 carbon atoms in its ring, provided that, in each case, the substituents are selected to provide a compound having an asymmetric structure, and further provided that R30 and R31 are covalently bonded to each other to provide the compound of formula (2) as a tetradentate ligand, and that R32 and R33 are covalently bonded to each other and R34 and R35 are covalently bonded to each other to provide the compound of formula (3) as a tetradentate ligand,
R10, R11 and R12 are as described above, more preferably, R10 and R12 are each xe2x80x94OC(O)xe2x80x94 or absent, and each R11 is alkyl, more preferably, xe2x80x94(CH2)nxe2x80x3xe2x80x94, or xe2x80x94CH(Cl)(CH2)mCH(Cl)xe2x80x94,
M is a first row transition metal atom,
n, nxe2x80x2, nxe2x80x3 and m are each numbers, wherein 1xe2x89xa6nxe2x89xa610, 1xe2x89xa6nxe2x80x2xe2x89xa615, 1xe2x89xa6nxe2x80x3xe2x89xa613, 1xe2x89xa6mxe2x89xa69 and
Axe2x80x2 is a counterion or nucleophile.
R30 and R31, R32 and R33, and R34 and R35 may, in each case, be directly covalently bonded to each other or may be indirectly covalently bonded to each other, such as, for example, via a bridging substituent.
As used herein, the terminology xe2x80x9cfirst row transition metal atomxe2x80x9d means an atom of an element listed in the first row of Groups 3-12 of the Periodic Table of elements, that is, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn.
In a highly preferred embodiment, the first row transition metal atom of the ligand metal atom complex is selected from Co, Cr and Mn.
In one preferred embodiment, the catalyst comprises at least one ligand-transition metal complex according to structure (2), wherein R30 and R31 are fused to form a 1,2-cyclohexylene group, Yxe2x80x2, Y2, X2, X4, X6 and X8 are each H, X1, X3, X5 and X7 are each t-butyl and M is Co.
In another preferred embodiment, the catalyst comprises at least one ligand-transition metal complex according to structure (3), wherein R32 and R33 are fused and R34 and R35 are fused to form respective 1,2-cyclohexylene groups, Y3, Y4, Y5, Y6, X9, X10, X11, X12, X13, X16, X17, and X20 are each H, R10 and R12 are each xe2x80x94OC(O)xe2x80x94, R11 is xe2x80x94(CH2)5xe2x80x94, X14, X15, X18 and X19 are each t-butyl, each M is Co and n is 1-10.
In some cases, the catalyst is available in an oxidation state other than the first oxidation state and is relatively inactive in catalyzing the desired reaction of the nucleophile and substrate. In such cases, the catalyst must be activated, for example, by changing the oxidation state of the catalyst, prior to conducting reaction step of the stereoselective chemical synthesis of the present invention. For example, in some preferred embodiments of the present invention, a Co(II)-salen complex is activated, for example, by contacting the catalyst in dichloromethane with acetic acid (xe2x80x9cHOAcxe2x80x9d) and air to form a Co(III)-salen complex.
In general, a mixture of the nucleophile, cyclic substrate, and a catalytic amount of chiral catalyst that is active in catalyzing the desired reaction of the substrate and nucleophile is maintained under conditions appropriate to allow the chiral catalyst to catalyze sterereoselective pening of the cyclic substrate by the nucleophile at the electrophilic tom of the substrate.
Kinetic resolution of enantiomers occurs with chiral catalysis of a ring-opening reaction of a racemic substrate. In one embodiment, one enantiomer can be reacted with the nucleophile to form a desired reaction product and the other enantiomer recovered as unreacted substrate. Alternatively, the undesired enantiomer can be reacted with the nucleophile and the desired enantiomer recovered unreacted from the reaction mixture.
Catalyst residue is present in the product mixture. The catalyst residue may include catalyst residue that is identical to the catalyst used to catalyze the desired reaction of the nucleophile and substrate and may include catalyst residue that is a degraded form, e.g., a reduced or oxidized form, of the catalyst used to catalyze the desired reaction.
The presence of catalyst residue in the product mixture during product isolation may be detrimental to the chemical or chiral purity of the product by catalyzing undesired degradation of the stereoisomerically enriched product, such as, for example:
(i) in a hydrolytic kinetic resolution reaction, the catalyst in the first oxidation state may be active in catalyzing an undesired racemization, for example, it has been found that under typical HKR reaction conditions, Co(III) complexes catalyze the racemization of resolved epichlorohydrin via HCl addition to the epoxide to form achiral 1,3-dichoro-2-propanol and the low-enantioselective reverse reaction,
(ii) in a reaction of a nucleophile, such as a phenol, with an epoxide that has a leaving group in the 3-position, the catalyst in the first oxidation state may be active in catalyzing undesired epoxide formation, for example: 
wherein LG=a leaving group, and
(iii) in a reaction of an epoxide with an electron-deficient phenol, the catalyst in the first oxidation state may be active in catalyzing equilibration of regioisomers via an undesired Smiles Rearrangement, for example: 
wherein EWG=an electron-withdrawing group.
In some embodiments, catalyst residue corresponding to the form of the catalyst used to catalyze the desired reaction may also be active in catalyzing less kinetically favored reactions that would degrade the desired product. For example, in the highly preferred embodiment of the HKR of epichlorohydrin, Co(III) salen catalyst is active in catalyzing the desired reaction of nucleophile and substrate and Co(III) salen catalyst residue is also active in catalyzing degradation of the stereoisomerically enriched product.
In other embodiments, catalyst residue corresponding to a degraded form of catalyst used to catalyze the desired reaction may be active in catalyzing reactions that degrade the desired product. For example, in the preferred embodiment of the HKR of styrene oxide, Co(III) salen catalyst is active in catalyzing the desired reaction of nucleophile and substrate and Co(II) salen catalyst residue generated during the reaction is active in catalyzing degradation of the stereoisomerically enriched product.
In either case, contact of the desired product with catalyst residue during isolation of the product can result in degradation of the stereoisomerically enriched product. Detriment to the chemical or chiral purity of the product that may arise due to the presence of catalyst residue during product isolation can be minimized by the process of the present invention.
Upon reaching stereoisomerically enriched product that exhibits a targeted degree of a stereoisomeric enrichment, such as for example, a targeted enantiomeric excess for the resolved product, the catalyst residue is treated, either chemically, electrochemically or a by combination thereof, to change the oxidation state of catalyst residue in a first oxidation state, in which the catalyst residue is active in catalyzing product degradation, from such first oxidation state, to a second oxidation state, in which the catalyst residue is relatively less active in catalyzing degradation of the product. In a preferred embodiment, the targeted degree of a stereoisomeric enrichment is production of a stereoisomerically enriched product that exhibits an enantiomeric excess of greater than or equal to 95%, more preferably, greater than or equal to 99%.
In one preferred embodiment, an organic or inorganic complexing agent effective in stabilizing the catalyst residue in the second oxidation state is added to the product mixture. The complexing agent may be any compound having a charged or uncharged component with a lone pair of electrons that is capable of binding with the transition metal complex and include, for example, ammonium hydroxide, amines, hydroxyamine, phosphines, sulfides, sulfoxides, amine N-oxides, amidines, quanidines, imidate esters phosphine oxides, carbon monoxide and cyanides.
In a preferred embodiment, the complexing agent comprises at least one amine according to the formula: 
wherein R40, R41 and R42 are each independently H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkaryl or heterocyclic, or may, alternatively, be fused with another one of the R40, R41 and R42 groups to form, together with the nitrogen atom to which they are attached, a heterocyclic 4 to 8-membered ring, any of which may be further substituted.
In a first embodiment, the oxidation state of catalyst residue is changed from the first oxidation state to the second oxidation state by reducing the catalyst residue.
In one preferred embodiment, the catalyst residue is chemically reduced by introducing an organic or inorganic reducing agent to the product mixture in an amount sufficient and under conditions appropriate to reduce any catalyst residue in the first oxidation state to catalyst residue in the second oxidation state. Suitable reducing agents may be any compound having sufficient reduction potential and reactivity to render it capable of reducing the active form of the ligand-transition metal atom complex, for example, a Co(III) complex or Cr(III) to a less reactive form of the complex, for example, a Co(II) complex or Cr(II) complex, under mild conditions and without adversely effecting the stereoisomerically enriched product. Typically, the reduction potential of the reagent used to reduce the active catalyst should be in the range of +0.1 to +0.6 v. This range is dependent upon the conditions of measurement as well as the reaction conditions under which the desired reaction occurs.
In another preferred embodiment, the reducing agent is selected from L-ascorbic acid, alcohols such as, for example, isopropanol, hydroquinone, and hydroquinone derivatives, such as for example, t-butylhydroquinone, catechol and catechol derivatives and mixtures thereof.
In a preferred embodiment, the reducing agent is contacted with the catalyst residue in an amount of from about 0.5 to about 10 mole equivalents of the reducing agent per mole of catalyst residue.
In general, the deactivation treatment step is conducted under mild conditions that will not adversely affect the product. In a preferred embodiment, the deactivation treatment step is conducted at a temperature of from about 5xc2x0 C. to about 50xc2x0 C., more preferably from about 15xc2x0 C. to about 25xc2x0 C.
In one preferred embodiment, Co(III)-salen complex is reduced by treatment with L-ascorbic acid. The treatment is conducted, for example, by contacting L-ascorbic acid with the Co(III)-salen complex. In a preferred embodiment, an amount of from about 0.5 to about 10 moles, more preferably from about 1 to about 2 moles, of L-ascorbic acid per mole of Co(III)-salen complex is contacted with the Co(III)-salen complex. In a preferred embodiment, the L-ascorbic acid is contacted with the Co(III)-salen complex at a temperature of about 5 to about 25xc2x0 C. for a time period of about 30 to about 180 minutes. Preferably, the treatment is conducted by adding the L-ascorbic acid to the reaction mixture and agitating the mixture under the appropriate treatment conditions. The Co(III)-salen complex is observed to undergo reduction to Co(II)-salen complex by a color change and the precipitation of the Co(II)-salen complex. This treatment reduces, to the point of eliminating, erosion of the enantiomeric excess of resolved product, as well as to fully retarding the formation of side products.
In an alternative embodiment, the catalyst residue is electrochemically reduced by applying an electrical current to the product mixture, in an amount sufficient and under conditions appropriate to reduce any catalyst residue in the first oxidation state to the second oxidation state. As a further alternative, the catalyst residue may be reduced by a combination of the addition of a chemical reducing agent to the reaction mixture and the application of an electric current to the product mixture.
In a second embodiment, the oxidation state of the catalyst residue is changed from the first oxidation state to the second oxidation state by oxidizing the catalyst residue.
In a preferred embodiment, the catalyst residue is chemically oxidized by introducing an organic or inorganic oxidizing agent to the product mixture in an amount sufficient and under conditions appropriate to oxidize any catalyst residue in the first oxidation state to relatively less active catalyst residue in the second oxidation state. Suitable oxidizing agents may be any compound having sufficient oxidation potential and reactivity to render it capable of oxidizing the active form of the catalyst residue, for example, Co(II), Cr(II), to a less reactive form of the complex, for example, Co(III), Cr(III), under mild conditions and without adversely effecting the stereoisomerically enriched product, and include, for example, hydrogen peroxide, peracids, persulfates, perborates, perchlorates, oxygen and air.
In a preferred embodiment, Co(II)(salen) catalyst residue from a hydrolytic kinetic resolution of styrene oxide is oxidized from a first oxidation state to a second oxidation state in the presence of an organic or inorganic complexing agent that is capable of stabilizing the Co(II)(salen) catalyst residue in the second oxidation state. The resulting Co(III)(salen) catalyst residue-ammonium complex is less active than the Co(II)(salen) catalyst residue in catalyzing reactions that erode the e.e. of the enantiomerically enriched product.
In a highly preferred embodiment, the catalyst residue is oxidized with oxygen, preferably supplied in the form of an air stream, in the presence of ammonium hydroxide to form a Co(III)(salen) catalyst residue-ammonium complex.
In an alternative embodiment, the catalyst residue is electrochemically oxidized by applying an electrical current to the product mixture, in an amount sufficient and under conditions appropriate to oxidize any catalyst residue in the first oxidation state to the second oxidation state. As a further alternative, the catalyst residue may be oxidized by a combination of the addition of a chemical oxidizing agent to the reaction mixture and the application of an electric current to the product mixture.
In typical large HKR reactions, it has not been possible to recycle the HKR catalyst. Following treatment according to the method of the present invention to deactivate the catalyst, the product can be purified and the deactivated catalyst can be recovered from the product mixture by conventional techniques, such as for example, distillation, filtration, extraction. Once recovered, the deactivated catalyst can be reactivated, that is, by changing the oxidation state of the recovered catalyst to increase the catalytic activity of the catalyst.
In the preferred embodiment of HKR of an epoxide using a Co(III)-salen complex, the resolved epoxide can typically be separated from the product mixture by distillation and the reduced activity Co(II)-salen complex can be recovered from the diol co-product by the addition of water and either filtration of the insoluble complex or extraction into an organic solvent. This recovered catalyst can be reactivated by oxidation to Co(III) by treatment with carboxylic or sulfonic acids in air or oxygen as previously described with no loss of reactivity or selectivity.
The treatment process allows the HKR to be performed, including the initial activation of the metal-salen complex, with or without an organic co-solvent.